title: AKT kinase activity is required for lithium to modulate mood-related behaviors in mice.
abstract: Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response-activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice-and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jen Q
authors.initials: JQ
authors.lastname: Pan
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lewis
authors.forename: Josh K
authors.initials: JK
authors.lastname: Ketterman
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Clore
authors.forename: Misha
authors.initials: M
authors.lastname: Riley
authors.forename: Keenan R
authors.initials: KR
authors.lastname: Richards
authors.forename: Erin
authors.initials: E
authors.lastname: Berry-Scott
authors.forename: Xiulin
authors.initials: X
authors.lastname: Liu
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Travis L
authors.initials: TL
authors.lastname: Biechele
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Edward M
authors.initials: EM
authors.lastname: Scolnick
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Petryshen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
mesh_terms: D000661:Amphetamine / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019964:Mood Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014162:Transfection / Q000379:methods
chemical_list: D018692:Antimanic Agents; D004791:Enzyme Inhibitors; D000661:Amphetamine; C494918:AKT1 protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride